Solid oral dosage form containing an enhancer

ABSTRACT

The invention relates to a solid oral dosage form comprising a pharmaceutically active ingredient in combination with an enhancer which enhances the bioavailability and/or the absorption of the active ingredient. Accordingly, a solid oral dosage form comprises a drug and an enhancer wherein the enhancer is a medium chain fatty acid ester, ether or salt or a derivative of a medium chain fatty acid, which is, preferably, solid at room temperature and which has a carbon chain length of from 6 to 20 carbon atoms. Preferably, the solid oral dosage form is controlled release dosage form such as a delayed release dosage form.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.12/172,707, filed Jul. 14, 2008, now issued as U.S. Pat. No. 8,323,689,which is a continuation of U.S. application Ser. No. 09/510,560, filedFeb. 22, 2000, now issued as U.S. Pat. No. 7,658,938, which claimspriority to U.S. Provisional Application Ser. No. 60/121,048, filed Feb.22, 1999. The entire contents of each of these applications isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a solid oral dosage form containingenhancers. In particular the invention relates to a solid oral dosageform comprising a pharmaceutically active ingredient in combination withan enhancer which enhances the bioavailability and/or the absorption ofthe active ingredient and which is a controlled release dosage form suchas a delayed release dosage form.

BACKGROUND OF THE INVENTION

The epithelial cells lining the lumenal side of the GIT are a majorbarrier to drug delivery following oral administration. However, thereare four recognised transport pathways which can be exploited tofacilitate drug delivery and transport: the transcellular, paracellular,carrier-mediated and transcytotic transport pathways. The ability of adrug, such as a conventional drug, a peptide, a protein, a macromoleculeor a nano- or microparticulate system, to “interact” with one or more ofthese transport pathways may result in increased delivery of that drugfrom the GIT to the underlying circulation.

Certain drugs utilise transport systems for nutrients which are locatedin the apical cell membranes (carrier mediated route). Macromoleculesmay also be transported across the cells in endocytosed vesicles(transcytosis route). However, many drugs are transported across theintestinal epithelium by passive diffusion either through cells(transcellular route) or between cells (paracellular). Most orallyadministered drugs are absorbed by passive transport. Drugs which arelipophilic permeate the epithelium by the transcellular route whereasdrugs that are hydrophilic are restricted to the paracellular route.

Paracellular pathways occupy less than 0.1% of the total surface area ofthe intestinal epithelium. Further, tight junctions, which form acontinuous belt around the apical part of the cells, restrict permeationbetween the cells by creating a seal between adjacent cells. Thus, oralabsorption of hydrophilic drugs such as peptides can be severelyrestricted. Other barriers to absorption of drugs may includehydrolysing enzymes in the lumen brush border or in the intestinalepithelial cells, the existence of the aqueous boundary layer on thesurface of the epithelial membrane which may provide an additionaldiffusion barrier, the mucus layer associated with the aqueous boundarylayer and the acid microclimate which creates a proton gradient acrossthe apical membrane. Absorption, and ultimately bioavailability, of adrug may also be reduced by other processes such as P-glycoproteinregulated transport of the drug back into the gut lumen and cytochromeP450 metabolism.

Therefore, new strategies for delivering drugs across the GIT celllayers are needed, particularly for hydrophilic drugs includingpeptides, proteins and macromolecular drugs.

Numerous potential absorption enhancers have been identified. Forinstance, medium chain glycerides have demonstrated the ability toenhance the absorption of hydrophilic drugs across the intestinal mucosa(Pharm. Res. (1994), 11, 1148-54). However, the importance of chainlength and/or composition is unclear and therefore their mechanism ofaction remains largely unknown. Sodium caprate has been reported toenhance intestinal and colonic drug absorption by the paracellular route(Pharm. Res. (1993) 10, 857-864; Pharm. Res. (1988), 5, 341-346). U.S.Pat. No. 4,656,161 (BASF AG) discloses a process for increasing theenteral absorbability of heparin and heparinoids by adding non-ionicsurfactants such as those that can be prepared by reacting ethyleneoxide with a fatty acid, a fatty alcohol, an alkylphenol or a sorbitanor glycerol fatty acid ester. U.S. Pat. No. 5,229,130 (CygnusTherapeutics Systems) discloses a composition which increases thepermeability of skin to a transdermally administered pharmacologicallyactive agent formulated with one or more vegetable oils as skinpermeation enhancers. Dermal penetration is also known to be enhanced bya range of sodium carboxylates [Int. J. of Pharmaceutics (1994), 108,141-148]. Additionally, the use of essential oils to enhancebioavailability is known (U.S. Pat. No. 566,386 AvMax Inc. and others).It is taught that the essential oils act to reduce either, or both,cytochrome P450 metabolism and P-glycoprotein regulated transport of thedrug out of the blood stream back into the gut.

Often, however, the enhancement of drug absorption correlates withdamage to the intestinal wall. Consequently, limitations to thewidespread use of GIT enhancers is frequently determined by theirpotential toxicities and side effects. Additionally and especially withrespect to peptide, protein or macromolecular drugs, the “interaction”of the GIT enhancer with one of the transport pathways should betransient or reversible, such as a transient interaction with or openingof tight junctions so as to enhance transport via the paracellularroute.

As mentioned above, numerous potential enhancers are known. However,this has not led to a corresponding number of products incorporatingenhancers. One such product currently approved for use in Sweden andJapan is the Doktacillin™ suppository [Lindmark et al. PharmaceuticalResearch (1997), 14, 930-935]. The suppository comprises ampicillin andthe medium chain fatty acid, sodium caprate (C10).

Provision of a solid oral dosage form which would facilitate theadministration of a drug together with an enhancer is desirable. Theadvantages of solid oral dosage forms over other dosage forms includeease of manufacture, the ability to formulate different controlledrelease and extended release formulations and ease of administration.Administration of drugs in solution form does not readily facilitatecontrol of the profile of drug concentration in the bloodstream. Solidoral dosage forms, on the other hand, are versatile and may be modified,for example, to maximise the extent and duration of drug release and torelease a drug according to a therapeutically desirable release profile.There may also be advantages relating to convenience of administrationincreasing patient compliance and to cost of manufacture associated withsolid oral dosage forms.

SUMMARY OF THE INVENTION

According to the present invention, a solid oral dosage form comprises adrug and an enhancer wherein the enhancer is a medium chain fatty acidsalt, ester, ether or a derivative of a medium chain fatty acid whichis, preferably, solid at room temperature and which has a carbon chainlength of from 6 to 20 carbon atoms; with the provisos that (i) wherethe enhancer is an ester of a medium chain fatty acid, said chain lengthof from 6 to 20 carbon atoms relates to the chain length of thecarboxylate moiety, and (ii) where the enhancer is an ether of a mediumchain fatty acid, at least one alkoxy group has a carbon chain length offrom 6 to 20 carbon atoms.

Preferably, the enhancer is a medium chain fatty acid salt, ester, etheror a derivative of a medium chain fatty acid which is, preferably, solidat room temperature and which has a carbon chain length of from 8 to 14carbon atoms; with the provisos that (i) where the enhancer is an esterof a medium chain fatty acid, said chain length of from 8 to 14 carbonatoms relates to the chain length of the carboxylate moiety, and (ii)where the enhancer is an ether of a medium chain fatty acid, at leastone alkoxy group has a carbon chain length of from 8 to 14 carbon atoms.More preferably, the enhancer is a sodium salt of a medium chain fattyacid, the medium chain fatty acid having a carbon chain length of from 8to 14 carbon atoms; the sodium salt being solid at room temperature.Most preferably, the enhancer is sodium caprylate, sodium caprate orsodium laurate. The drug and enhancer can be present in a ratio of from1:100000 to 10:1 (drug:enhancer) preferably, from 1:1000 to 10:1.

In a preferred embodiment of the invention the drug is a macromoleculesuch as a peptide, protein, oligosaccharide or polysaccharide includingTRH, unfractionated heparin, low molecular weight heparin, insulin,luteinising hormone-releasing hormone (LHRH), leuprolide acetate,goserelin, naferelin, buserelin, cyclosporin, calcitonin, vasopressin,desmopressin, an antisense oligonucleotide, alendronate, etidronate orsalts thereof.

The solid oral dosage form can be a tablet, a mutiparticulate or acapsule. The multiparticulate can be in the form of a tablet orcontained in a capsule. The tablet can be a single or multilayer tablethaving compressed multiparticulate in one, all or none of the layers. Itis preferably a controlled release dosage form. More preferably, it is adelayed release dosage form. The dosage form can be coated with apolymer, preferably a rate-controlling or a delayed release polymer. Thepolymer can also be compressed with the enhancer and drug to form amatrix dosage form such as a controlled release matrix dosage form. Apolymer coating can then be applied to the matrix dosage form.

Other embodiments of the invention include the process of making thesolid oral dosage forms, methods of treating a condition byadministering the solid oral dosage forms to a patient and use of a drugand enhancer in the manufacture of a medicament.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of the sodium salts of C8, C10, C12, C14, C18and C18:2 with ³H-TRH on TEER (Ωcm²) in Caco-2 monolayers at time 0 andat 30 min. Intervals up to 2 hours as described in Example 1.

FIG. 2 shows the effect of the sodium salts of C8, C10, C12, C14, C18and C18:2 on P_(app) for ³H-TRH transport in Caco-2 monolayers asdescribed in Example 1.

FIG. 3 shows the serum TRH concentration-time profiles followinginterduodenal bolus dose of 500 μg TRH with NaC8 or NaC10 (35 mg)enhancer present according to the closed loop rat model described inExample 1.

FIG. 4 shows the serum TRH concentration-time profiles followinginterduodenal bolus dose of 1000 μg TRH with NaC8 or NaC10 (35 mg)enhancer present according to the closed loop rat model described inExample 1.

FIG. 5 shows the APTT response over a period of 4 hours followingadministration of USP heparin (1000 IU) with different sodium caprate(C10) levels (10 and 35 mg) according to the closed loop rat modeldescribed in Example 2.

FIG. 6 shows the anti-factor Xa response over a period of 5 hoursfollowing administration of USP heparin (1000 IU) in the presence ofdifferent sodium caprylate (C8) levels (10 mg and 35 mg) according tothe closed loop rat model described in Example 2.

FIG. 7 shows the anti-factor Xa response over a period of five hoursfollowing administration of USP heparin (1000 IU) in the presence ofdifferent sodium caprate (C10) levels (10 mg and 35 mg) according to theclosed loop rat model described in Example 2.

FIG. 8 shows the mean anti-factor Xa response in dogs over a period oftime up to 8 hours following administration of: a) s.c. USP heparinsolution (5000 IU); b) oral uncoated instant release tablet formulationcontaining USP heparin (90000 IU) and NaC10; c) oral uncoated instantrelease tablet formulation containing USP heparin (90000 IU) and NaC8;and d) oral uncoated sustained release tablet formulation containing USPheparin (90000 IU) and sodium caprate prepared according to theinvention as described in Example 2.

FIG. 9 shows the anti-factor Xa response over a period of three hoursfollowing intraduodenal administration to rats of phosphate bufferedsaline solutions of parnaparin sodium (low molecular weight heparin(LMWH)) (1000 IU), in the presence of 35 mg of different enhancers[sodium caprylate (C8), sodium nonanoate (C9), sodium caprate (C10),sodium undecanoate (C11), sodium laurate (C12)] and different 50:50binary mixtures of enhancers, to rats (n=8) in an open loop model. Thereference product comprised administering 250 IU parnaparin sodiumsubcutaneously. The control solution comprised administering a solutioncontaining 1000 IU parnaparin sodium without any enhancerintraduodenally.

FIG. 10 shows the mean plasma levels of leuprolide over a period ofeight hours following intraduodenal administration of solutions ofleuprolide (20 mg) containing different levels of sodium caprate (0.0 g(control), 0.55 g, 1.1 g) to dogs.

FIG. 11 shows the mean anti-factor Xa response in dogs over a period ofeight hours following oral administration of parnaparin sodium (90,000IU) in the presence of 550 mg sodium caprate, as both a solution (10 ml)and an instant release tablet dosage form.

FIG. 12 shows the mean anti-factor Xa response in humans over a periodof 24 hours following oral administration of parnaparin sodium (90,000IU) in the presence of sodium caprate, as both a solution (240 ml) andan instant release tablet dosage form

FIG. 13 shows the mean anti-factor Xa response in humans over a periodof 24 hours following intrajejunal administration of 15 ml solutionscontaining different doses parnaparin sodium (20,000 IU, 45,000 IU,90,000 IU) in the presence of different doses of sodium caprate (0.55 g,1.1 g, 1.65 g)

FIG. 14 shows the mean anti-factor Xa response in dogs over a period of8 hours following oral administration of 45,000 IU parnaparin sodium as:(a) instant release capsules containing 0.55 g sodium caprate, (b)Eudragit L coated rapidly disintegrating tablets containing 0.55 gsodium caprate and (c) Eudragit L coated rapidly disintegrating tabletswithout enhancer.

FIG. 15 shows the mean anti-factor Xa response in dogs over a period of8 hours following co-administration of 45,000 IU LMWH and 0.55 g sodiumcaprate orally, intrajejunally and intracolonically compared tosubcutaneous administration.

DETAILED DESCRIPTION OF THE INVENTION

As used in this specification and appended claims, the singular forms“a”, “an” and “the” include plural referents unless the content clearlydictates otherwise. Thus, for example, reference to “an enhancer”includes a mixture of one or more enhancers, reference to “a drug”includes reference to one or more drugs, and the like.

As used herein, the term “enhancer” refers to a compound (or mixture ofcompounds) which is capable of enhancing the transport of a drug,particularly a hydrophilic and/or macromolecular drug across the GIT inan animal such as a human, wherein the enhancer is a medium chain fattyacid salt, ester or ether or a derivative of a medium chain fatty acidthat is, preferably, solid at room temperature and that has a carbonchain length of from 6 to 20 carbon atoms; with the provisos that (i)where the enhancer is an ester of a medium chain fatty acid, said chainlength of from 6 to 20 carbon atoms relates to the chain length of thecarboxylate moiety, and (ii) where the enhancer is an ether of a mediumchain fatty acid, at least one alkoxy group has a carbon chain length offrom 6 to 20 carbon atoms. Preferably, the enhancer is a sodium salt ofa medium chain fatty acid. Most preferably, the enhancer is sodiumcaprate.

As used herein, a “derivative of a medium chain fatty acid” comprises afatty acid derivative having at least one carbon chain of from 6 to 20carbon atoms in length. This carbon chain may be characterised byvarious degrees of saturation. In other words, the carbon chain may be,for example, fully saturated or partially unsaturated (i.e. containingone or more carbon-carbon multiple bonds). The term “fatty acidderivative” is meant to encompass acyl derivatives such as esters, acidhalides, anhydrides, amides and nitriles, and also ethers and glyceridessuch as mono-, di- or tri-glycerides. The term “fatty acid derivative”is meant to further encompass medium chain fatty acids wherein the endof the carbon chain opposite the acid group (or derivative) is alsofunctionalised with one of the above mentioned moieties (i.e. ester,acid halide, anhydride, amide, nitrile, ether and glyceride moieties).Such difunctional fatty acid derivatives thus include for examplediacids and diesters (the functional moieties being of the same kind)and also difunctional compounds comprising different functionalmoieties, such as amino acids and amino acid derivatives (for example amedium chain fatty acid, or an ester or a salt thereof, comprising anamide moiety at the opposite end of the fatty acid carbon chain to theacid (or ester or salt thereof).

As used herein, the term “drug” includes any drug, includingconventional drugs, appropriate for administration via the oral route toan animal including a human. The term “drug” also explicitly includesthose entities that are poorly absorbed via the oral route includinghydrophilic drugs or macromolecular drugs such as peptides, proteins,oligosaccharides, polysaccharides or hormones including, but not limitedto, insulin, calcitonin, calcitonin gene regulating protein, atrialnatriuretic protein, colony stimulating factor, betaseron,erythropoletin (EPO), interferons, somatropin, somatotropin,somatostatin, insulin-like growth factor (somatomedins), luteinizinghormone releasing hormone (LHRH), tissue plasminogen activator (TPA),thyrotropin releasing hormone (TRH), growth hormone releasing hormone(GHRH), antidiuretic hormone (ADH) or vasopressin and analogues thereofsuch as for example desmopressin, parathyroid hormone (PTH), oxytocin,estradiol, growth hormones, leuprolide acetate, goserelin acetate,naferelin, buserelin, factor VIII, interleukins such as interleukin-2,and analogues thereof and anti-coagulant agents such as heparin,heparinoids, low molecular weight heparin, hirudin, and analoguesthereof, bisphosphonates including alendronate and etidronate,pentassacharides including anticoagulent pentassacharides, antigens,adjuvants and the like. The drug compound itself may be in the form ofnano-, micro- or larger particles in crystalline or amorphous form.

The drug can be included in a nano- or microparticulate drug deliverysystems in which the drug is entrapped, encapsulated by, associatedwith, or attached to a nano- or microparticle. Preferably, the drug isin a crystalline or amorphous form or in a form that does not includebeing associated with a nano- or microparticle.

As used herein, a “therapeutically effective amount of a drug” refers toan amount of drug that elicits a therapeutically useful response in ananimal, preferably a mammal, most preferably a human.

As used herein, a “therapeutically effective amount of an enhancer”refers to an amount of enhancer that allows for uptake oftherapeutically effective amounts of the drug via oral administration.It has been shown that the effectiveness of an enhancer in enhancing thegastrointestinal delivery of poorly permeable drugs is dependent on thesite of administration (see Examples 6, 7 and 12), the site of optimumdelivery being dependent on the drug and enhancer.

A solid oral dosage form according to the present invention may be atablet, a multiparticulate or a capsule. A preferred solid oral dosageform is a delayed release dosage form which minimises the release ofdrug and enhancer in the stomach, and hence the dilution of the localenhancer concentration therein, and releases the drug and enhancer inthe intestine. A particularly preferred solid oral dosage form is adelayed release rapid onset dosage form. Such a dosage form minimisesthe release of drug and enhancer in the stomach, and hence the dilutionof the local enhancer concentration therein, but releases the drug andenhancer rapidly once the appropriate site in the intestine has beenreached, maximising the delivery of the poorly permeable drug bymaximising the local concentration of drug and enhancer at the site ofabsorption

The term “tablet” as used herein includes, but is not limited to,immediate release (IR) tablets, sustained release (SR) tablets, matrixtablets, multilayer tablets, multilayer matrix tablets, extended releasetablets, delayed release tablets and pulsed release tablets any or allof which may optionally be coated with one or more coating materials,including polymer coating materials, such as enteric coatings,rate-controlling coatings, semi-permeable coatings and the like. Theterm “tablet” also includes osmotic delivery systems in which a drugcompound is combined with an osmagent (and optionally other excipients)and coated with a semi-permeable membrane, the semi-permeable membranedefining an orifice through which the drug compound may be released.Tablet solid oral dosage forms particularly useful in the practice ofthe invention include those selected from the group consisting of IRtablets, SR tablets, coated IR tablets, matrix tablets, coated matrixtablets, multilayer tablets, coated multilayer tablets, multilayermatrix tablets and coated multilayer matrix tablets. A preferred tabletdosage form is an enteric coated tablet dosage form. A particularlypreferred tablet dosage form is an enteric coated rapid onset tabletdosage form.

Capsule solid oral dosage forms particularly useful in the practice ofthe current invention include those selected from the group consistingof instant release capsules, sustained release capsules, coated instantrelease capsules, coated sustained release capsules including delayedrelease capsules. A preferred capsule dosage form is an enteric coatedcapsule dosage form. A particularly preferred capsule dosage form is anenteric coated rapid onset capsule dosage form.

The term “multiparticulate” as used herein means a plurality of discreteparticles, pellets, mini-tablets and mixtures or combinations thereof.If the oral form is a multiparticulate capsule, such hard or softgelatin capsules can suitably be used to contain the multiparticulate.Alternatively a sachet can suitably be used to contain themultiparticulate. If desired, the multiparticulate may be coated with alayer containing rate controlling polymer material. A multiparticulateoral dosage form according to the invention may comprise a blend of twoor more populations of particles, pellets, or mini-tablets havingdifferent in vitro and/or in vivo release characteristics. For example,a multiparticulate oral dosage form may comprise a blend of an instantrelease component and a delayed release component contained in asuitable capsule.

Alternatively, the multiparticulate and one or more auxiliary excipientmaterials can be compressed into tablet form such as a multilayertablet. Typically, a multilayer tablet may comprise two layerscontaining the same or different levels of the same active ingredienthaving the same or different release characteristics. Alternatively, amultilayer tablet may contain different active ingredient in each layer.Such a tablet, either single layered or multilayered, can optionally becoated with a controlled release polymer so as to provide additionalcontrolled release properties. A preferred multiparticulate dosage formcomprises a capsule containing delayed release rapid onset minitablets.A particularly preferred multiparticulate dosage form comprises adelayed release capsule comprising instant release minitablets. A mostpreferred multiparticulate dosage form comprises a capsule comprisingdelayed release granules. A most particularly preferred multiparticulatedosage form comprises a delayed release capsule comprising instantrelease granules.

A number of preferred embodiments of the invention will now bedescribed. In each case the drug may be present in any amount which issufficient to elicit a therapeutic effect and, where applicable, may bepresent either substantially in the form of one optically pureenantiomer or as a mixture, racemic or otherwise, of enantiomers. Thedrug compound is suitably present in any amount sufficient to elicit atherapeutic effect. As will be appreciated by those skilled in the art,the actual amount of drug compound used will depend on the potency ofthe drug compound in question. The amount of drug compound may suitablybe in the range of from about 0.5 μg to about 1000 mg. The enhancer issuitably present in any amount sufficient to allow for uptake oftherapeutically effective amounts of the drug via oral administration.Preferably the drug and the enhancer are present in a ratio of from1:100000 to 10:1 (drug:enhancer), preferably the ratio is from 1:1000 to10:1. The actual ratio of drug to enhancer used will depend on thepotency of the drug compound and the enhancing activity of the enhancer.

In a first embodiment, a solid oral dosage form according to theinvention comprises a drug and an enhancer in admixture compressed intoa tablet.

In a second embodiment, a solid oral dosage form according to theinvention comprises a drug, an enhancer and a rate controlling polymermaterial in admixture compressed into a tablet. The term “ratecontrolling polymer material” as used herein includes hydrophilicpolymers, hydrophobic polymers and mixtures of hydrophilic and/orhydrophobic polymers that are capable of controlling or retarding therelease of the drug compound from a solid oral dosage form of thepresent invention. Suitable rate controlling polymer materials includethose selected from the group consisting of hydroxyalkyl cellulose suchas hydroxypropyl cellulose and hydroxypropyl methyl cellulose;poly(ethylene) oxide; alkyl cellulose such as ethyl cellulose and methylcellulose; carboxymethyl cellulose, hydrophilic cellulose derivatives;polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; celluloseacetate butyrate; cellulose acetate phthalate; cellulose acetatetrimellitate; polyvinyl acetate phthalate; hydroxypropylmethyl cellulosephthalate; hydroxypropylmethyl cellulose acetate succinate; polyvinylacetaldiethylamino acetate; poly(alkylmethacrylate) and poly(vinylacetate). Other suitable hydrophobic polymers include polymers and/orcopolymers derived from acrylic or methacrylic acid and their respectiveesters, zein, waxes, shellac and hydrogenated vegetable oils.Particularly useful in the practice of the present invention are polyacrylic acid, poly acrylate, poly methacrylic acid and poly methacrylatepolymers such as those sold under the Eudragit tradename (Rohm GmbH,Darmstadt, Germany) specifically Eudragit® L, Eudragit® S, Eudragit® RL,Eudragit® RS coating materials and mixtures thereof. Some of thesepolymers can be used as delayed release polymers to control the sitewhere the drug is released. They include poly methacrylate polymers suchas those sold under the Eudragit tradename (Rohm GmbH, Darmstadt,Germany) specifically Eudragit® L, Eudragit® S, Eudragit® RL, Eudragit®RS coating materials and mixtures thereof.

In a third embodiment, a solid oral dosage form according to theinvention comprises a multilayer table. Typically such a multilayertablet may comprise a first layer containing a drug and an enhancer inan instant release form and a second layer containing a drug and anenhancer in a sustained, extended, controlled or modified release form.In an alternative embodiment, a multilayer tablet may comprise a firstlayer containing a drug and a second layer containing an enhancer. Eachlayer may independently comprise further excipients chosen to modify therelease of the drug or the enhancer. Thus the drug and the enhancer maybe released from the respective first and second layers at rates whichare the same or different. Alternatively, each layer of the multilayertablet may comprise both drug and enhancer in the same or differentamounts.

A fourth embodiment a solid oral dosage form according to the inventioncomprises a drug and an enhancer in admixture in the form of amultiparticulate. The drug and enhancer may be contained in the same ordifferent populations of particles, pellets or mini-tablets making upthe multiparticulate. If the solid oral dosage form is amultiparticulate, sachets and capsules such as hard or soft gelatincapsules can suitably be used to contain the multiparticulate. Amultiparticulate solid oral dosage form according to the invention maycomprise a blend of two or more populations of particles, pellets ormini-tablets having different in vitro and/or in vivo releasecharacteristics. For example, a multiparticulate oral dosage form maycomprise a blend of an immediate release component and a delayed releasecomponent contained in a suitable capsule.

In the case of any of the above-mentioned embodiments, a controlledrelease coating may be applied to the final dosage form (capsule,tablet, multilayer tablet etc.). The controlled release coating maytypically comprise a rate controlling polymer material as defined above.The dissolution characteristics of such a coating material may be pHdependent or independent of pH.

The various embodiments of the solid oral dosage forms of the inventionmay further comprise auxiliary excipients such as for example diluents,lubricants, disintegrants, plasticisers, anti-tack agents, opacifyingagents, pigments, flavourings and such like. As will be appreciated bythose skilled in the art, the exact choice of excipients and theirrelative amounts will depend to some extent on the final dosage form.

Suitable diluents include for example pharmaceutically acceptable inertfillers such as microcrystalline cellulose, lactose, dibasic calciumphosphate, saccharides, and/or mixtures of any of the foregoing.Examples of diluents include microcrystalline cellulose such as thatsold under the Trademark Avicel (FMC Corp., Philadelphia, Pa.) forexample Avicel™ pH101, Avicel™ pH102 and Avicel™ pH112; lactose such aslactose monohydrate, lactose anhydrous and Pharmatose DCL21; dibasiccalcium phosphate such as Emcompress; mannitol; starch; sorbitol;sucrose; and glucose.

Suitable lubricants, including agents that act on the flowability of thepowder to be compressed are, for example, colloidal silicon dioxide suchas Aerosil™ 200; talc; stearic acid, magnesium stearate, and calciumstearate.

Suitable disintegrants include for example lightly crosslinked polyvinylpyrrolidone, corn starch, potato starch, maize starch and modifiedstarches, croscarmellose sodium, cross-povidone, sodium starch glycolateand combinations and mixtures thereof.

Example 1 TRH Containing Tablets

(a) Caco-2 Monolayers.

Cell Culture:

Caco-2 cells were cultured in Dulbecco's Modified Eagles Medium (DMEM)4.5 g/L glucose supplemented with 1% (v/v) non-essential amino acids;10% foetal calf serum and 1% penicillin/streptomycin. The cells werecultured at 37° C. and 5% CO₂ in 95% humidity. The cells were grown andexpanded in standard tissue culture flasks and were passaged once theyattained 100% confluence. The Caco-2 cells were then seeded onpolycarbonate filter inserts (Costar; 12 mm diameter, 0.4 m pore size)at a density of 5×10⁵ cells/cm² and incubated in six well culture plateswith a medium change every second day. Confluent monolayers between day20 and day 30 seeding on filters and at passages 30-40 were usedthroughout these studies.

Transepithelial Transport Studies:

The effects sodium salts of various MCFAs on the transport of ³H-TRH(apical to basolateral flux) was examined as follows: 15.0 μCi/ml (0.2μM) ³H-TRH was added apically at time zero for TRH flux experiments. Thetransport experiments were performed in Hanks Balanced salt solution(HBSS) containing 25 mMN-[2-hydroxyethyl]-piperazine-N′-[2-ethanesulfonic acid] (HEPES) buffer,pH 7.4 at 37° C. Due to variations in solubilities, variousconcentrations of the different MCFA sodium salts and various apicalbuffers were used as shown in Table 1. In all cases the basolateralchamber contained regular HBSS+HEPES,

TABLE 1 Concentrations and buffers used for various MCFA sodium saltsMCFA salt* Conc. (mM) Buffer NaC8:0 0.32 HBSS + HEPES NaC10:0 0.40 Ca²⁺free HBSS NaC12:0 3.77 PBS** NaC14:0 1.44 PBS NaC18:0 0.16 HBSS + HEPESNaC18:2 0.16 HBSS + HEPES *In the nomenclature CX:Y for a MCFA salt, Xindicates the length of the carbon chain and Y indicates the position ofunsaturation, if any. **PBS - phosphate buffer solution.

After removing the cell culture medium, the monolayers were placed inwells containing prewarmed HBSS (37° C.); 1 ml apically and 2 mlbasolaterally. Monolayers were incubated at 37° C. for 30 mins. Then attime zero, apical HBSS was replaced with the relevant apical testsolution containing the radiolabelled compounds with and without theenhancer compound. Transepithelial electrical resistance (TEER) of themonolayer was measured at time zero and at 30 min intervals up to 120min using a Millicell ERS chopstix apparatus (Millipore (U.K.) Ltd.,Hertfordshire, UK) with Evom to monitor the integrity of the monolayer.The plates were placed on an orbital shaker in an incubator (37° C.).Transport across the monolayers was followed by basolateral sampling (1ml) at 30 min. intervals up to 120 mins. At each 30 min. interval eachinsert was transferred to a new well containing 2 ml fresh prewarmedHBSS. Apical stock radioactivity was determined by taking 10 μl samplesat t=0 and t=120 mins. Scintillation fluid (10 ml) was added to eachsample and the disintegrations per min. of each sample were determinedin a Wallac System 1409 scintillation counter. Mean values for ³H-TRHconcentrations were calculated for the apical and basolateral solutionsat each time point. The apparent permeability coefficients werecalculated using the method described by Artursson [Artursson P., J.Pharm. Sci. 79:476-482 (1990).

FIG. 1 shows the effect of C8, C10, C12, C14, C18 and C18:2 sodium saltswith ³H-TRH on TEER (Ωcm²) in Caco-2 monolayers over 2 hours. The datafor the C8, C10, C14 and C18 indicate minimal reduction in TEER comparedto the control. While the data for C12 indicates some cell damage(reduction in TEER), this reduction is probably a result of the higherconcentration of enhancer used in this.

FIG. 2 shows the effect of C8, C10, C12, C14, C18 and C18:2 sodium saltson P_(app) for ³H-TRH across in Caco-2 monolayers. Compared to thecontrol, the sodium salts of C8, C10, C12 and C14 showed considerableincreases in the permeability constant, P_(app), at the concentrationsused. It is noted that the high P_(app) value observed for the C12 saltmay be indicative of cell damage at this high enhancer concentration.

Mitochondrial Toxicity Assay:

Mitochondrial dehydrogenase (MDH) activity was assessed as a marker ofcell viability using a method based on the colour change of tetrazoliumsalt in the presence MDH. Cells were harvested, counted and seeded on 96well plates at an approximate density of 10⁸ cells/ml (100 μl of cellsuspension per well). The cells were then incubated at 37° C. for 24hours in humidified atmosphere, 5% CO₂. A number of wells were treatedwith each MCFA sodium salt solution at the concentrations shown in Table1 and the plate was incubated for 2 hours. After incubation 10 μl of MTTlabelling reagent was added to each well for 4 hours. Solubilisationbuffer (100 μl; see Table 1) was added to each well and the plate wasincubated for a further 24 hours. Absorbance at 570 nm of each samplewas measured using a spectrophotometer (Dynatech MR7000).

(b) In Vivo Administration (Closed Loop Rat Model).

in vivo rat closed loop studies were modified from the methods ofDoluisio et al. [Doluisio J. T., et al: Journal of PharmaceuticalScience (1969), 58, 1196-1200] and Brayden et al. [Brayden D.: DrugDelivery Pharmaceutical News (1997) 4(1)]. Male Wistar rats (weightrange 250 g-350 g) were anaesthetised with ketaminehydrochloride/acepromazine. A mid-line incision was made in the abdomenand a segment of the duodenum (7-9 cm of tissue) was isolated about 5 cmdistal from the pyloric sphincter, taking care to avoid damage tosurrounding blood vessels. The sample solutions (PBS containing C8 orC10 (35 mg) and TRH (500 μg and 1000 μg)) and control (PBS containingTRH only (500 μg and 1000 μg)) warmed to 37° C. were administereddirectly into the lumen of the duodenal segment using a 26 G needle. Allintraduodenal dose volumes (for samples and control) were 1 ml/kg. Theproximal end of the segment was ligated and the loop was sprayed withisotonic saline (37° C.) to provide moisture and then replaced in theabdominal cavity avoiding distension. The incision was closed withsurgical clips. A group of animals were administered TRH in PBS (100 μgin 0.2 ml) by subcutaneous injection as a reference.

FIG. 3 shows the serum TRH concentration-time profiles followinginterduodenal bolus dose of 500 μg TRH with NaC8 or NaC10 (35 mg)enhancer present, according to the closed loop rat model. FIG. 4 showsthe serum TRH concentration-time profiles following interduodenal bolusdose of 1000 μg TRH with NaC8 or NaC10 (35 mg) enhancer present,according to the closed loop rat model. From FIGS. 3 and 4 it can beseen that the presence of the enhancer in each case significantlyincreases the serum levels of TRH over the control TRH solutionindicating increased absorption of the drug in the presence of theenhancer.

(c) Tableting.

Having established the enhancing effect of NaC8 and NaC10 on TRH insolution, immediate release (IR) and sustained release (SR) TRH tabletsand the like may be prepared. IR and SR formulations are detailed inTables 2 and 3 below.

TABLE 2 THR IR tablet formulation details (all amounts in wt. %) Mag.Micro. Silica Stea- Lac- Disinte- Cellu- TRH NaC₈ NaC₁₀ Dioxide ratetose grant lose PVP 0.64 70.36 — 0.5 0.5 20 8 — — 1.27 69.73 — 0.5 0.520 8 — — 1.23 — 67.64 0.5 0.5 20 8 — 2.13 2.42 — 66.45 0.5 0.5 — 8 202.13 2.42 — 66.45 0.5 0.5 20 8 — 2.13

TABLE 3 THR SR tablet formulation details (all amounts in wt. %) Micro-Silica Magnesium cystalline TRH NaC₁₀ Dioxide Stearate HPMC^((a))Cellulose PVP 1.41 77.59 0.5 0.5 20 — — 1.05 57.95 0.5 0.5 20 20 — 2.6873.94 0.5 0.5 20 — 2.37

Example 2 Heparin Containing Tablets

(a) Closed-Loop Rat Segment.

The procedure carried out in Example 1 (a) above was repeated using USPheparin in place of TRH and dosing intralleally rather thanintraduodenally. A mid-line incision was made in the abdomen and thedistal end of the ileum located (about 10 cm proximal to the ileo-caecaljunction). 7-9 cm of tissue was isolated and the distal end ligated,taking care to avoid damage to surrounding blood vessels. Heparinabsorption as indicated by activated prothrombin time (APTT) responsewas measured by placing a drop of whole blood (freshly sampled from thetail artery) on the test cartridge of Biotrack 512 coagulation monitor.APTT measurements were taken at various time points. FIG. 5 shows theAPTT response of USP heparin (1000 iu) at different sodium caprate (C10)levels (10 and 35 mg). Using APTT response as an indicator of heparinabsorption into the bloodstream, it is clear that there is a significantincrease in absorption in the presence of sodium caprate compared to thecontrol heparin solution containing no enhancer.

Citrated blood samples were centrifuged at 3000 rpm for 15 mins. toobtain plasma for anti-factor X_(a) analysis. FIG. 6 shows theanti-factor Xa response of USP heparin (1000 iu) in the presence ofsodium caprylate (C8, 10 mg and 35 mg). FIG. 7 shows the anti-factor Xaresponse of USP heparin (1000 iu) in the presence of sodium caprate(C10, 10 mg and 35 mg). The control in each case is a solution of thesame heparin concentration containing no enhancer. The significantincrease in anti-factor X_(a) activity observed for NaC8 (at 35 mg dose)and NaC10 (at both 10 mg and 35 mg doses) is indicative of the increasein heparin absorption relative to the control heparin solutioncontaining no enhancer.

(b) Tableting.

(i) IR Tablets.

Instant release (IR) tablets containing heparin sodium USP (197.25IU/mg, supplied by Scientific Protein Labs., Waunkee, Wis.) and anenhancer (sodium caprylate, NaC8; sodium caprate, NaC10, supplied byNapp Technologies, New Jersey) were prepared according to the formulaedetailed in Table 4 by direct compression of the blend using a Manesty(E) single tablet press. The blend was prepared as follows: heparin, theenhancer and tablet excipients (excluding where applicable colloidalsilica dioxide and magnesium stearate) were weighed out into acontainer. The colloidal silica dioxide, when present, was sievedthrough a 425 μm sieve into the container, after which the mixture wasblended for four minutes before adding the magnesium stearate andblending for a further one minute.

TABLE 4 Formulation data for IR tablets containing heparin and enhancer(all amounts in wt. %) Silica Magne- Batch Hep- diox- sium Man- Disinte-No. NaC₈ NaC₁₀ arin ide stearate nitol grant^((a)) PVP^((b)) 1 65.7 —13.3 0.5 0.5 20.0 — — 2 62.2 — 16.8 0.5 0.5 20.0 — — 3 57.49 — 21.91 0.10.5 20.0 — — 4 75.66 — 15.34 0.5 0.5 — 8.0 — 5 — 62.0 37.5 0.5 — — — — 6— 49.43 30.07 0.5 — 20.0 — — 7 — 31.29 25.94 0.5 0.5 40.0 1.77 “—”indicates “not applicable”; ^((a))Disintegrant used was sodium starchglycolate; ^((b))PVP = polyvinyl pyrrolidone

The potency of tablets prepared above was tested using a heparin assaybased on the azure dye determination of heparin. The sample to beassayed was added to an Azure A dye solution and the heparin content wascalculated from the absorbance of the sample solution at 626 nm. Tabletdata and potency values for selected batches detailed in Table 4 aregiven in Table 5.

Dissolution profiles for IR tablets according to this Example inphosphate buffer at pH 7.4 were determined by heparin assay, sampling atvarious time points.

Heparin/Sodium Caprylate:

Tablets from batches 1 and 2 gave rapid release yielding 100% of thedrug compound at 15 minutes. Tablets from batch 4 also gave rapidrelease yielding 100% release at 30 minutes.

Heparin/Sodium Caprate:

Tablets from batches 5 and 6 gave rapid release yielding 100% of thedrug compound at 15 minutes.

TABLE 5 Tablet data and potency values for IR heparin tablets ActualTablet Disinte- heparin Potency Batch weight Hardness gration potency as% of No. Enhancer (mg) (N) time (s) (mg/g) label 1 NaC₈ 431 ± 5 85 ± 4 —145.67 109 2 NaC₈  414 ± 14 82 ± 9 — 175.79 105 3 NaC₈ 650 ± 4  71 ± 12552 166.4 119 4 NaC₈ 377 ± 2  58 ± 10 — 168.04 110 5 NaC₁₀  408 ± 21 79± 7 — 394.47 105 6 NaC₁₀ 490 ± 6 124 ± 10 — 323.33 108 7 NaC₁₀  584 ± 12 69 ± 22 485 143.0 102

(ii) SR Tablets.

Using the same procedure as used in (I) above, sustained release (SR)tablets were prepared according to the formulae shown in Table 6. Thepotency of controlled release tablets was determined using the sameprocedure as in (i) above. Tablet details and potency for selectedbatches are shown in Table 7.

Dissolution profiles for SR tablets according this Example weredetermined by heparin assay at pH 7.4, sampling at various time points.

Heparin/Sodium Caprylate:

Dissolution data for batches 8, 9 and 11 are shown in Table 8. From thisdata it can be seen that heparin/sodium caprylate SR tablets with 15%Methocel K100 LV with and without 5% sodium starch glycolate (batches 8& 9) gave a sustained release with 100% release occurring between 3 and4 hours. Batch 11 containing 10% mannitol gave a faster release.

Heparin/Sodium Caprate:

Dissolution data for batches 13 and 14 are shown in Table 8. From thisdata it can be seen that heparin/sodium caprate SR tablets with 20%Methocel K100 LV (batch 13) gave a sustained release of the drugcompound over a six hour period. Where Methocel K15M (batch 14) was usedin place of Methocel K100 LV release of the drug compound was incompleteafter 8 hours.

TABLE 6 Formulation data for SR tablets containing heparin and enhancer(all amounts in wt. %) Batch Silica Mag. Disinte- Micro. No. NaC₈ NaC₁₀Heparin dioxide stearate HPMC^((a)) grant^((b)) Mannitol cellulosePVP^((c)) 8 69.84 — 14.16 0.5 0.5 15 — — — — 9 65.68 — 13.32 0.5 0.5 155.0 — — — 10 65.68 — 13.32 0.5 0.5 12 8.0 — — — 11 65.68 — 13.32 0.5 0.510.0 — 10.0 — — 12 53.77 — 20.48 — 1.0 14.85 — — 9.9 — 13 — 56.2 23.30.5 — 20.0 — — — — 14 — 56.2 23.3 0.5 — 20.0* — — — — 15 — 41.63 34.520.5 1.0 20.0 — — — 2.35 “—” indicates “not applicable”;^((a))Hydroxypropylmethyl cellulose: Methocel K100LV in each case except“*” in which Methocel K15M was employed; ^((b))Disintegrant used wassodium starch glycolate; ^((c))PVP = polyvinyl pyrrolidone;

TABLE 7 Table data and potency values for SR heparin tablets Actualheparin Batch Tablet Hardness Disintegra- potency No. Enhancer weight(mg) (N) tion time (s) (mg/g) 8 NaC₈ 397 ± 5 52 ± 11 — — 9 NaC₈  436 ±11 40 ± 10 — 140.08 10 NaC₈ 384 ± 4 42 ± 12 — — 11 NaC₈ 400 ± 8 72 ± 16— 129.79 12 NaC₈ 683 ± 9 84 ± 17 3318 147.10 13 NaC₁₀  491 ± 14 69 ± 7 — — 14 NaC₁₀  456 ± 13 47 ± 4  — — 15 NaC₁₀  470 ± 29 — 2982 148.20

TABLE 8 Dissolution data for selected batches of SR tablets % Release(as % of label) Batch 8 Batch 9 Batch 11 Batch 13 Batch 14 Time (min)(NaC₈) (NaC₈) (NaC₈) (NaC₁₀) (NaC₁₀) 0 0 0 0 0 0 15 22.9 21.2 45.3 18.85.7 30 37.3 30.8 72.3 45.0 11.6 60 57.8 54.5 101.9 44.8 11.2 120 92.290.8 109.4 65.2 20.0 240 109.5 105.8 96.4 83.1 33.9 360 — — — 90.3 66.0480 — — — 102.7 82.8

(iii) Enteric Coated Tablets.

Tablets from batches 7 and 15 were enterically coated with a coatingsolution as detailed in Table 9. Tablets were coated with 5% w/w coatingsolution using a side vented coating pan (Freund Hi-Coata).Disintegration testing was carried out in a VanKel disintegration testerVK100E4635. Disintegration medium was initially simulated gastric fluidpH1.2 for one hour and then phosphate buffer pH7. The disintegrationtime recorded was the time from introduction into phosphate buffer pH7.4to complete disintegration. The disintegration time for entericallycoated tablets from batch 7 was 34 min. 24 sec, while for enteric coatedtablets from batch 15 the disintegration time was 93 min. 40 sec.

TABLE 9 Enteric coating solution Component Amount (wt. %) Eudragit ®12.5 49.86 Diethyl phthlate 1.26 Isopropyl alcohol 43.33 Talc 2.46 Water3.06(c) Dog Study.

Tablets from batches 3, 7 and 15 in Tables 5 and 6 above were dosedorally to groups of five dogs in a single dose crossover study. Eachgroup was dosed with (1) orally administered uncoated IR tabletscontaining 90000 IU heparin and 550 mg NaC10 enhancer (batch 7); (2)orally administered uncoated IR tablets containing 90000 IU heparin and550 mg NaC8 enhancer (batch 3); (3) orally administered uncoated SRtablets containing 90000 IU heparin and 550 mg NaC10 enhancer (batch 15)and (4) s.c. administered heparin solution (5000 IU, control). Bloodsamples for anti-factor Xa to analysis were collected from the jugularvein at various times points. Clinical assessment of all animals pre-and post-treatment indicated no adverse effects on the test subjects.FIG. 8 shows the mean anti-factor X_(a) response for each treatment,together with the s.c. heparin solution reference. The data in FIG. 8shows an increase in the plasma anti-factor Xa activity for all of theformulations according to the invention. This result indicates thesuccessful delivery of bioactive heparin using both NaC8 and NaC10enhancers. Using IR formulations and an equivalent dose of heparin, alarger anti-factor Xa response was observed with the NaC10 enhancer, inspite of the lower dose of NaC10 relative to NaC8 administered (NaC10dose was half that of NaC8). The anti-factor Xa response can besustained over a longer time profile relative to the IR formulations byformulating as SR tablets.

Example 3 Effect of Enhancers on the Systemic Availability of LowMolecular Weight Heparin (LMWH) after Intraduodenal Administration inRats

Male Wistar rats (250 g-350 g) were anaesthetised with a mixture ofketamine hydrochloride (80 mg/kg) and acepromazine maleate (3 mg/kg)given by intra-muscular injection. The animals were also administeredwith halothane gas as required. A midline incision was made in theabdomen and the duodenum was isolated.

The test solutions, comprising parnaparin sodium (LMWH) (Opocrin SBA,Modena, Italy) with or without enhancer reconstituted in phosphatebuffered saline (pH 7.4), were administered (1 ml/kg) via a cannulainserted into the intestine approximately 10-12 cm from the pyloris. Theintestine was kept moist with saline during this procedure. Followingdrug administration, the intestinal segment was carefully replaced intothe abdomen and the incision was closed using surgical clips. Theparenteral reference solution (0.2 ml) was administered subcutaneouslyinto a fold in the back of the neck.

Blood samples were taken from a tail artery at various intervals andplasma anti; factor Xa activity was determined. FIG. 9 shows the meananti-factor Xa response to over a period of 3 hours followingintraduodenal administration to rats of phosphate buffered salinesolutions of parnaparin sodium (LMWH) (1000 IU), in the presence of 35mg of different enhancers [sodium caprylate (C8), sodium nonanoate (C9),sodium caprate (C10), sodium undecanoate (C11), sodium laurate (C12)]and different 50:50 binary mixtures of enhancers, to rats (n=8) in anopen loop model. The reference product comprised administering 250 IUparnaparin sodium subcutaneously. The control solution comprisedadministering a solution containing 1000 IU parnaparin sodium withoutany enhancer intraduodenally.

FIG. 9 shows that the systemic delivery of LMWH in the absence ofenhancer is relatively poor after intraduodenal administration to rats;however, the co-administration of the sodium salts of medium chain fattyacids significantly enhanced the systemic delivery of LMWH from the ratintestine

Example 4 Effect of Enhancers on the Systemic Availability of Leuprolideafter Intraduodenal Administration in Dogs

Beagle dogs (10-15 Kg) were sedated with medetomidine (80 μg/kg) and anendoscope was inserted via the mouth, oesophagus and stomach into theduodenum. The test solutions (10 ml), comprising leuprolide acetate(Mallinckrodt Inc, St. Louis, Mo.) with or without enhancerreconstituted in deionised water were administered intraduodenally viathe endoscope. Following removal of the endoscope, sedation was reversedusing atipamezole (400 g/kg). The parenteral reference solutionscomprising 1 mg Leuprolide reconstituted in 0.5 ml sterile water wereadministered intravenously and subcutaneously respectively.

Blood samples were taken from the jugular vein at various intervals andplasma leuprolide levels were determined. The resulting mean plasmaleuprolide levels are shown in FIG. 10. The results show that, althoughthe systemic delivery of leuprolide when administered intraduodenallywithout enhancer is negligible, coadministration with enhancer resultedin a considerable enhancer dose dependent enhancement in the systemicdelivery of leuprolide; a mean % relative bioavailability of 8% observedfor at the upper dose of enhancer.

Example 5 Effect of Enhancers on the Systemic Availability of LMWH afterOral Administration in Dogs

(a) Granulate Manufacture

A 200 g blend containing parnaparin sodium (47.1%), sodium caprate(26.2%), mannitol (16.7%) and Explotab™ (Roquette Freres, Lestrem,France) (10.0%) was granulated in a Kenwood Chef mixer using water asthe granulating solvent. The resulting granulates were tray dried in anoven at 67-68° C. and size reduced through 1.25 mm, 0.8 mm and 0.5 mmscreens respectively in an oscillating granulator. The actual potency ofthe resulting granulate was determined as 101.1% of the label claim.

(b) 30,000 IU LMWH/183 mg Sodium Caprate Instant Release TabletManufacture

The granulate described above was bag blended with 0.5% magnesiumstearate for 5 minutes. The resulting blend was tabletted using 13 mmround concave tooling on a Riva Piccalo tablet press to a target tabletcontent of 30,000 IU parnaparin sodium and 183 mg sodium caprate. Thetablets had a mean tablet hardness of 108 N and a mean tablet weight of675 mg. The actual LMWH content of the tablets was determined as 95.6%of label claim.

Disintegration testing was carried out on the tablets. One tablet wasplaced in each of the six tubes of the disintegration basket. Thedisintegration apparatus was operated at 29-30 cycles per minute usingde-ionised water at 37° C., Tablet disintegration was complete in 550seconds.

(c) 90,000 IU LMWH 10.55 g Sodium Caprate Solution Manufacture

90,000 IU parnaparin sodium and 0.55 g sodium caprate were individuallyweighed into glass bottles and the resulting powder mixture wasreconstituted with 1.0 ml water,

(d) Dog Biostudy Evaluation

90,000 IU parnaparin sodium and 550 mg sodium caprate was administeredas both a solution dosage form (equivalent to 10 ml of the abovesolution composition) and a fast disintegrating tablet dosage form(equivalent to 3 tablets of the above tablet composition) in a singledose, non randomised, cross-over study in a group of six female beagledogs (9.5-14.4 Kg) with a seven day washout between treatments. Asubcutaneous injection containing 5000 IU parnaparin sodium was used asthe reference.

Blood samples were taken from the jugular vein at various intervals andanti-factor Xa activity was determined. Data was adjusted for baselineanti-factor Xa activity. The resulting mean plasma anti-factor Xa levelsare summarised in FIG. 11. Both the tablet and solution dosage formsshowed good responses when compared with the subcutaneous reference leg.The mean delivery, as determined by plasma antifactor Xa levels, ofparnaparin sodium from the solid dosage form was considerably greaterthan that from the corresponding solution dosage form.

Example 6 Effect of Enhancers on the Systemic Availability of LMWH afterOral Administration in Humans

(a) Granulate Manufacture

Parnaparin sodium (61.05%), sodium caprate (33.95%) and polyvinylpyrrolidone (Kollidon 30, BASF AG, Ludwigshafen, Germany) (5.0%) weremixed for 5 minutes in a Gral 10 prior to the addition of water, whichwas then gradually added, with mixing, using a peristaltic pump untilall the material was apparently granulated.

The resultant granulates were tray dried in an oven at either 50° C. for24 hours. The dried granules were milled through a 30 mesh screen usinga Fitzmill M5A

(b) 45,000 IU LMWH/275 mg Sodium Caprate Instant Release TabletManufacture

The parnaparin sodium/sodium caprate/polyvinyl pyrrolidone granulate(78.3%) was blended for 5 minutes with mannitol (16.6%), explotab (5.0%)and magnesium stearate (1.0%) in a 10 liter V Cone blender. The potencyof the resulting blend (480.41 mg/g) was 100.5% of the label claim.

The blend was tabletted using 13 mm round normal concave tooling on thePiccola 10 station press in automatic mode to a target content of 45,000IU LMWH and 275 mg sodium caprate. The resulting instant release tabletshad a mean tablet weight of 1027 mg, a mean tablet hardness of 108 N anda potency of 97% label claim. The tablets showed a disintegration timeof up to 850 seconds and 100% dissolution into pH 1.2 buffer in 30minutes.

(c) 90,000 IU LMWH/550 mg Sodium Caprate Solution Manufacture

Two instant tablets, each containing 45,000 IU LMWH and 275 mg sodiumcaprate, were reconstituted in 30 ml water.

(d) Human Biostudy Evaluation

90,000 IU LMWH and 550 mg sodium caprate was orally administered to 12healthy human volunteers as both a solution dosage form (equivalent to30 ml of the above solution dosage form) and as a solid dosage form(equivalent to 2 tablets of the above composition) in an open label,three treatment, three period study with a seven day washout betweeneach dose; Treatments A (Instant Release Tablets) and B (Oral Solution)were crossed over in a randomised manner whereas Treatment C (6,400 IUFluxum™ SC (Hoechst Marion Roussel), a commercially available injectableLMWH product) was administered to the same subjects as a single block.

Blood samples were taken at various intervals and anti-factor X aactivity was determined. The resulting mean anti-factor Xa levels areshown in FIG. 12. Treatments A and B exhibited unexpectedly lowresponses when compared with the subcutaneous reference treatment.However it should be noted that the mean delivery of LMWH, as measuredby plasma anti-factor Xa levels, was considerably higher from the soliddosage form than that from the corresponding solution dosage form forwhich a mean % bioavailability of only 0.9% was observed.

Example 7 Effect of Enhancers on the Systemic Availability of LMWH afterIntrajejunal Administration in Humans

(a) Solution Manufacture

The following LMWH/sodium caprate combinations were made with 15 mldeionised water:

(i) 20,000 IU LMWH, 0.55 g Sodium Caprate;

(ii) 20,000 IU LMWH, 1.1 g Sodium Caprate;

(iii) 45,000 IU LMWH, 0.55 g Sodium Caprate;

(iv) 45,000 IU LMWH, 1.1 g Sodium Caprate;

(v) 45,000 IU LMWH, 1.65 g Sodium Caprate

(b) Human Biostudy Evaluation

15 ml of each of the above solutions was administered intrajejunally viaa nasojejunal intubation in an open label, six treatment periodcrossover study in up to 11 healthy human volunteers. 3,200 IU Fluxum™SC was included in the study as a subcutaneous reference. Blood sampleswere taken at various Intervals and anti-factor X a activity wasdetermined. The resulting mean anti-factor Xa levels are shown in FIG.13.

It should be noted that the mean % relative bioavailability for eachtreatment in the current study was considerably higher than the mean %bioavailability observed for the solution dosage form in Example 6; mean% bioavailabilities ranging from 5% to 9% were observed for thetreatments in the current study suggesting that the preferred LMWH oraldosage form containing sodium caprate should be designed to minimiserelease of drug and enhancer in the stomach and maximise the release ofdrug and enhancer in the small intestine.

Example 8 Manufacture of Delayed Release Tablet Dosage Form ContainingLMWH and Enhancer

(a) LMWH/Sodium Caprate Granulate Manufacture

A 500 g batch of parnaparin sodium:sodium caprate (0.92:1) wasgranulated in a Gral 10 using a 50% aqueous solution of Kollidon 30 asthe granulating solvent. The resulting granulate was dried for 60minutes in a Niro Aeromatic Fluidised Bed Drier at a final producttemperature of 25° C. The dried granulate was milled through a 30 meshscreen in a Fitzmill M5A. The potency of the resulting dried granulatewas determined as 114.8% of the label claim.

(b) 22,500 IU LMWH/275 mg Sodium Caprate Instant Release TabletManufacture

The above granulate (77.5%) was added to mannitol (16%), Polyplasdone™XL (ISP, Wayne, N.J.) (5%) and Aerosil™ (1%) (Degussa, Rheinfelden,Germany) in a 10 l V coned blender and blended for 10 minutes. Magnesiumstearate (0.5%) was added to the resulting blend and blending wascontinued for a further 3 minutes.

The resulting blend was tabletted on Piccola tablet press using 13 mmround normal concave tooling to a mean tablet weight of 772 mg and amean tablet hardness of 140 N.

The actual potency of the resulting tablets was determined as 24,017 IULMWH per tablet.

(c) 22,500 IU LMWH/275 mg Sodium Caprate Delayed Release TabletManufacture

The above tablets were coated with a coating solution containingEudragit L 12.5 (50%), isopropyl alcohol (44.45%), dibutyl sebecate(3%), talc (1.3%), water (1.25%) in a Hicoater to a final % weight gainof 5.66%.

The resulting enteric coated tablets remained intact after 1 hourdisintegration testing in pH 1.2 solution; complete disintegration wasobserved in pH 6.2 medium after 32-33 minutes.

Example 9 Manufacture of Instant Release Capsule Dosage Form ContainingLMWH and Enhancer

(a) 22,500 IU LMWH/275 mg Sodium Caprate Instant Release CapsuleManufacture

The granulate from the previous example, part a, was hand filled intoSize 00 hard gelatin capsules to a target fill weight equivalent to thegranulate content of the tablets in the previous example.

Example 10 Manufacture of Delayed Release Tablet Dosage Form ContainingLMWH without Enhancer

(a) LMWH Granulate Manufacture

A 500 g batch of parnaparin sodium:Avicel™ pH 101 (0.92:1) (FMC, LittleIsland, Co. Cork, Ireland) was granulated in a Gral 10 using a 50%aqueous solution of Kollidon 30 as the granulating solvent. Theresulting granulate was dried for 60 minutes in a Niro AeromaticFluidised Bed Drier at an exhaust temperature of 38° C. The driedgranulate was milled through a 30 mesh screen in a Fitzmill M5A. Thepotency of the resulting dried granulate was determined as 106.5% of thelabel claim.

(b) 22,500 IU LMWH Instant Release Tablet Manufacture

The above granulate (77.5%) was added to mannitol (21%) and aerosil (1%)in a 25 L V coned blender and blended for 10 minutes. Magnesium stearate(0.5%) was added to the resulting blend and blending was continued for afurther 1 minute.

The resulting blend was tabletted on Piccola tablet press using 13 mmround normal concave tooling to a mean tablet weight of 671 mg and amean tablet hardness of 144 N.

The actual potency of the resulting tablets was determined as 21,651 IULMWH per tablet.

(c) 22,500 IU LMWH Delayed Release Tablet Manufacture

The above tablets were coated with a coating solution containingEudragit L 12.5 (50%), isopropyl alcohol (44.45%), dibutyl sebecate(3%), talc (1.3%) and water (1.25%) in a Hicoater to a final % weightgain of 4.26%.

The resulting enteric coated tablets remained intact after 1 hourdisintegration testing in pH 1.2 solution; complete disintegration wasobserved in pH 6.2 medium in 22 minutes.

Example 11 Effect of Controlled Release Dosage Form Containing Enhanceron to the Systemic Availability of LMWH after Oral Administration inDogs

(a) Dog Study Evaluation

45,000 IU LMWH was administered to 8 beagle dogs (10.5-13.6 Kg), in anopen label, non randomised crossed over block design, as (a) an instantrelease capsule dosage form containing 550 mg sodium caprate (equivalentto 2 capsules manufactured according to Example 9) (b) a delayed releasetablet dosage containing 550 mg sodium caprate (equivalent to twotablets manufactured according to Example 8) and (c) a delayed releasetablet dosage not containing any enhancer (equivalent to 2 tabletsmanufactured according to Example 10). 3,200 IU Fluxum™ SC was includedin the study as a subcutaneous reference.

Blood samples were taken from the jugular vein at various intervals andanti-factor X a activity was determined. The resulting mean anti-factorXa levels are shown in FIG. 14.

It should be noted that in the absence of sodium caprate, the systemicdelivery of LMWH was minimal from the delayed release solid dosage formwithout enhancer. In contrast, a good anti-factor Xa response wasobserved after administration of the delayed release LMWH solid dosageform containing sodium caprate. The mean anti-factor Xa response fromthe delayed release dosage form containing sodium caprate wasconsiderably higher than that from the instant release dosage formcontaining the same level of drug and enhancer.

Example 12 Effect of the Site of Administration on the SystemicAvailability of LMWH in Dogs after Co-Administration with Enhancer

Four beagle dogs (10-15 Kg) were surgically fitted with catheters to thejejunum and colon respectively. The test solutions (10 ml) comprisingLMWH with sodium caprate reconstituted in deionised water wereadministered to the dogs either orally or via the intra-intestinalcatheters. 3,200 IU Fluxum™ SC was included in the study as asubcutaneous reference.

Blood samples were taken from the brachial vein at various intervals andanti-factor Xa activity was determined. The resulting mean anti-factorXa levels are shown in FIG. 15. The results show that the intestinalabsorption of LMWH in the presence of enhancer is considerably higherthan absorption from the stomach.

Example 13 Leuprolide Containing Tablets

Following the same type of approach as used in Examples 1 and 2,leuprolide-containing IR tablets may be prepared according to theformulations detailed in Table 10.

TABLE 10 IR tablet formulations containing Leuprolide (all amounts inwt. %) Micro- Silica Magnesium Lac- Disinte- cystalline Leuprolide NaC10Dioxide Stearate tose grant Cellulose 0.05 68.82 0.5 0.5 20 8 — 0.1370.87 0.5 0.5 — 8 20 0.13 68.75 0.5 0.5 20 8 —

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingfigures. Such modifications are intended to fall within the scope of theappended claims.

What is claimed is:
 1. A method of treating a medical conditioncomprising administering to a patient suffering from said condition atherapeutically effective amount of a hydrophilic or macromolecular drugused in treating the condition together with an absorption enhancer,wherein said drug and said absorption enhancer are in the form of asolid oral dosage form which consists of a pharmaceutical compositionconsisting of: (A) a therapeutically effective amount of saidhydrophilic or macromolecular drug; (B) one or more absorptionenhancers, each of which: (i) is a solid at room temperature; (ii) is asalt of a medium chain fatty acid having a carbon length of from 8 to 14carbon atoms; and (iii) is present in the dosage form such that theratio of the drug to the one or more absorption enhancers is 1:100,000to 10:1; (C) one or more excipients selected from the group consistingof rate-controlling polymeric materials, diluents, lubricants,disintegrants, plasticizers, anti-tack agents, opacifying agents,pigments, and flavorings; and optionally, a controlled release coating;wherein the solid oral dosage form is a tablet, a multiparticulatecompressible to form a tablet, or a capsule containing amultiparticulate compressible to form a tablet.
 2. The method of claim1, wherein the absorption enhancer is a sodium salt of a medium chainfatty acid.
 3. The method of claim 2, wherein the absorption enhancer isselected from the group consisting of sodium caprylate, sodium caprateand sodium laurate.
 4. The method of claim 2, wherein the absorptionenhancer is sodium caprate.
 5. The method of claim 1, wherein the dosageform is a tablet.
 6. The method of claim 1, wherein the pharmaceuticalcomposition has thereon an enteric coating.
 7. The method of claim 6,wherein the enteric-coated composition is a tablet.
 8. The method ofclaim 6, wherein the enteric-coated composition is a capsule whichcontains said pharmaceutical composition.
 9. The method of claim 1,wherein the drug is an anticoagulant.
 10. The method of claim 1, whereinthe drug is a bisphosphonate.
 11. The method of claim 1, wherein thedrug is a peptide or protein.
 12. The method of claim 1, wherein thedrug is an oligosaccharide or polysaccharide.
 13. The method of claim 1,wherein the drug is a hormone.
 14. The method of claim 5, wherein thetablet is an instant-release tablet.
 15. The method of claim 6, whereinthe enteric coating comprises a polymer selected from the groupconsisting of poly(acrylic acid), polyacrylate, poly(methacrylic acid),polymethacrylate, and mixtures thereof.
 16. The method of claim 1,wherein the pharmaceutical composition includes at least two absorptionenhancers.
 17. The method of claim 1, wherein one of the excipients is arate-controlling polymeric material.
 18. The method of claim 1, whereinone of the excipients is a diluent which is an inert filler selectedfrom the group consisting of microcrystalline cellulose, lactose,dibasic calcium phosphate, saccharides and mixtures of any of theforegoing.
 19. The method of claim 1, wherein one of the excipients is alubricant selected from the group consisting of colloidal silicondioxide, talc, magnesium stearate, calcium stearate, and stearic acid.20. The method of claim 1, wherein one of the excipients is adisintegrant selected from the group consisting of lightly crosslinkedpolyvinylpyrrolidone, corn starch, potato starch, maize starch andmodified starches, croscarmellose sodium, crospovidone, and sodiumstarch glycolate.